Received for publication February 13, 2007.
Revised May 23, 2007.
Accepted for publication May 24, 2007.

Involvement of up-regulation of hepatic breast cancer resistance protein in decreased plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38) by coadministration of S-1 in rats

Abstract

The safety and efficacy of combination therapy with irinotecan (CPT-11, 7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycamptothecin) and S-1 composed of tegafur, a prodrug of 5-fluorouracil, gimeracil and potassium oxonate, have been confirmed in patients with colorectal cancer. Previously, we showed that oral coadministration of S-1 decreased the plasma concentration of both CPT-11 and its metabolites in an advanced colorectal cancer patient. The aim of this study was to clarify the mechanism of drug interaction using both in vivo and in vitro methods. Rats were orally administered S-1 (10 mg/kg) once a day for 7 consecutive days. On day 7, CPT-11 (10 mg/kg) was administered by i.v. injection. Coadministration of S-1 affected the pharmacokinetic behavior of CPT-11 and its metabolites, with a decrease in the C_max and AUC of the active metabolite, SN-38 (7-ethyl-10-hydroxycampothecin) lactone form. Furthermore, the rate of biliary excretion of SN-38 carboxylate form increased upon coadministration of S-1. In the liver, the level of breast cancer resistance protein (BCRP), but not P-glycoprotein and multidrug resistance-associated protein 2, was elevated after administration of S-1. Enzymatic conversion of CPT-11 to SN-38 by carboxylesterase (CES) was unaffected by the liver microsomes of rats treated with S-1. In addition, components of S-1 did not inhibit the hydrolysis of p-nitrophenylacetate, a substrate of CES, in the S9 fraction of HepG2 cells. Therefore, the mechanism of drug interaction between CPT-11 and S-1 appears to involve up-regulation of BCRP in the liver, resulting in an increased rate of biliary excretion of SN-38 accompanied by a decrease in the C_max and AUC of SN-38.

Key words: ABC transporters, anticancer agents, biliary excretion, drug interactions, pharmacokinetics